Abstract
BackgroundFetal growth restriction (FGR) is a worldwide problem, and a major cause of perinatal morbidity. The precise molecular mechanisms involved in placental development and function during FGR remain poorly understood. Circular RNAs (circRNAs) are important biological molecules associated with disease pathogenesis. However, the role of circRNAs in FGR has not been well studied.MethodscircRNA expression profiles in placental tissues with and without FGR were identified by circRNA microarray. circRNA expression was verified by quantitative reverse-transcription PCR (RT-qPCR) assay. The effect of hsa_circ_0000848 and hsa-miR-6768-5p on HTR-8 cell apoptosis, migration, and invasion was evaluated. The association between hsa_circ_0000848 and hsa-miR-6768-5p was confirmed by dual luciferase activity and anti-AGO2 RNA immunoprecipitation (RIP) assays. Protein levels were examined via western blotting.ResultsRT-qPCR results showed that hsa_circ_0000848 expression was significantly down-regulated in FGR placenta. Hsa_circ_0000848 overexpression and hsa-miR-6768-5p inhibitor suppressed apoptosis, and promoted cell migration and invasion. In addition, hsa_circ_0000848 overexpression and hsa-miR-6768-5p inhibitor increased the protein abundance of BCL2, MMP2 and MMP9, and decreased the protein abundance of cleaved caspase-3, cleaved caspase-9, and BAX, whereas hsa_circ_0000848 knockdown caused the opposite effect. Moreover, a significant increase in hsa-miR-6768-5p expression and a negative correlation between hsa_circ_0000848 and hsa-miR-6768-5p were identified in the FGR tissues. Luciferase reporter and RIP assay results revealed binding of hsa-miR-6768-5p to hsa_circ_0000848. Furthermore, hsa-miR-6768-5p overexpression eliminated the effect of hsa_circ_0000848 overexpression in HTR-8 cells.Conclusionshsa_circ_0000848 expression is significantly down-regulated in the FGR placenta. hsa_circ_0000848 promotes trophoblast cell migration and invasion, and inhibits cell apoptosis via the sponging of hsa-miR-6768-5p. Our study provided a novel insight into mechanisms underlying the pathogenesis of FGR, as well as into new strategies for the treatment of FGR.
Highlights
Fetal growth restriction (FGR), known as intrauterine growth restriction (IUGR), is defined as a fetal birth weight less than 2,500 g after 37 weeks gestation, a fetal weight less than two standard deviations below the mean weight for the same gestational age, or a fetal weight below the 10th percentile of the normal weight for the same gestational age (Sharma et al, 2016a; Figueras and Gratacos, 2017; Nardozza et al, 2017)
The birth weights in the FGR and normal groups were 2,231 ± 352 g, and 3,385.75 ± 429 g, respectively, and were significantly differenct (P < 0.0001)
The red points in the Volcano plots represent the statistically significantly differentially expressed circRNAs between the FGR and normal groups based on statistical criteria of fold-change >1.5 and P < 0.05 (Figure 1B)
Summary
Fetal growth restriction (FGR), known as intrauterine growth restriction (IUGR), is defined as a fetal birth weight less than 2,500 g after 37 weeks gestation, a fetal weight less than two standard deviations below the mean weight for the same gestational age, or a fetal weight below the 10th percentile of the normal weight for the same gestational age (Sharma et al, 2016a; Figueras and Gratacos, 2017; Nardozza et al, 2017). FGR is a worldwide problem, and the major cause of multifarious mortality and morbidity in the neonatal and fetal population (Sharma et al, 2016b; Nardozza et al, 2017). The etiology and pathogenesis of FGR is complex; maternal, fetal, and uteroplacental factors are involved (Gynecologists, 2013; Nardozza et al, 2017). The precise molecular mechanisms regulating trophoblast cells in FGR are poorly understood. Identification of potential molecular FGR markers in the placenta, and investigating their roles in both the regulation of inappropriate invasion and the excessive apoptosis of trophoblast cells, is essential to fully understand the etiology and pathogenesis of FGR. The role of circRNAs in FGR has not been well studied
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